Paediatric Lung Transplantation
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1 Paediatric Lung Transplantation Cross Canada Rounds Dr. Lucy Perrem Respiratory Medicine Fellow Dec 21 st 2017
2 Objectives 1. Overview of paediatric lung transplantation 2. Discuss acute management and complications in context of recent cases in HSC
3 Incidence Goldfarb S et al, J Heart Lung Transplant, 2015; Sweet S, Resp Care 2017
4 Indications ISHLT registry data Sweet S, Respiratory Care, 2017
5 Contraindications Faro et al, Am J Transplant 2007; Sweet S, Resp Care 2017
6 Contraindications Faro et al, Am J Transplant 2007; Sweet S, Resp Care 2017
7 Survival Goldfarb S et al, J Heart Lung Transplant, 2015
8 Case 1
9 NS 12 year old Idiopathic pulmonary arterial hypertension (dx age 6)
10 Pulmonary Hypertension mean pulmonary artery pressure 25 mmhg at rest (WHO) Group 1 Pulmonary arterial hypertension (PAH) Group 2 PH due to left heart disease Group 3 PH due to chronic lung disease and/or hypoxemia Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH) Group 5 PH due to unclear multifactorial mechanisms
11
12
13 NS 12 year old Idiopathic pulmonary arterial hypertension Rx: Treprostinil (Remodulin ) s/c continuous infusion Tadalafil (Adcirca ) 40mg daily Macitentan (Opsumit ) 10mg PO daily Oxygen 1.5L/min (nocturnal + with exercise) Listed Feb 2016
14 NS 12 year old Symptoms++ Echo: Severely dilated and severely reduced RV systolic fxn. RVSp > 2/3 rd systemic pressure (78mmHg) ECG: : Biatrial enlargement. right ventricular hypertrophy.
15 NS 12 year old Transplanted Aug 2017 Pre-op exam: HR108 RR18 BP96/57 SpO2 96% CVS: Increased JVP, Loud P2. Normal pulses, CRT<2sec, no peripheral edema Resp: equal a/e bilat, no adventitious sounds GIT: SNT, no HSM
16 Double Lung Transplant Bilateral sequential lung transplant with end-toend bronchial to bronchial anastomosis - on ECMO
17 Double Lung Transplant Bilateral sequential lung transplant with end-to-end bronchial to bronchial anastomosis - on ECMO Virtual crossmatch positive, high PRAs
18 Preventing hyperacute rejection Step 1 - Virtual crossmatch screening for the presence of recipient pre-formed anti-hla antibodies to the prospective donor HLA type. decision to proceed with transplant Step 2 - An actual crossmatch with donor cells and recipient serum (flow cytometry) Usually resulted AFTER transplant
19 Double Lung Transplant Bilateral sequential lung transplant with end-to-end bronchial to bronchial anastomosis - on ECMO Virtual crossmatch positive, high PRAs Receives plasmapheresis in OR Receives plasmapheresis in ICU Then actual crossmatch negative. No DSAs detected
20 Double Lung Transplant Triple immunosuppression: IS: Prednisone, tacrolimus, MMF
21 Double Lung Transplant Treated with pip-tazobactam for donor +ve staph aureus and E. Coli RLL consolidation - donor consolidation EBV: D+/R+ and CMV: D-/R- Candida prophylaxis
22 Double Lung Transplant Leaves hospital on day 14.
23 Complications
24 Sweet S et al. Pediatric Lung Transplantation. In Kendig and Chernick s Disorders of the Respiratory Tract in Children. 8th Ed. 2006
25 Post-transplant phase 1) Surgical Bleeding anastomotic and non-anastomotic airway stenosis anastomotic dehiscence lobar torsion Pneumothorax Nerve injury Phrenic nerve Recurrent laryngeal nerve Vagus nerve Tejwani V, et al.. Chest Grasemann H, et al. Springer International (in press)
26 Immediate/Early Complications 1) Surgical Bleeding anastomotic and non-anastomotic airway stenosis anastomotic dehiscence lobar torsion pneumothorax Phrenic nerve injury Vagus nerve injury 2) Primary Graft Dysfunction w/i 72h ischemia-reperfusion injury dx exclusion Tejwani V, et al.. Chest Grasemann H, et al. Springer International (in press)
27 Immediate/Early Complications 3) Immunological complications Hyperacute rejection Acute cellular rejection Antibody mediated rejection Tejwani V, et al.. Chest Grasemann H, et al. Early Postoperative Management, Springer International (in press)
28 Immediate/Early Complications 3) Immunological complications Hyperacute rejection Acute cellular rejection Antibody mediated rejection 4) Infectious complications Bacterial/ Viral CMV EBV Herpes Fungal Aspergillus Candida PCP Tejwani V, et al.. Chest Grasemann H, et al. Early Postoperative Management, Springer International (in press) Sweet C, Resp Care. 2017
29 Immediate/Early Complications 5) Iatrogenic Transfusion related acute lung injury Medication SE Diabetes Renal impairment Neurological complications Leukopenia De Perrot et al, Am J Crit Care Med. 2003
30 Immediate/Early Complications 5) Iatrogenic Transfusion related acute lung injury Medication SE 6) Other Pulmonary edema pulmonary arterial or venous thrombus Donor lung injury Pulmonary aspiration Gastroparesis/GIT dysmotility SVT De Perrot et al, Am J Crit Care Med. 2003
31 Sept 5 Returns to clinic 5 days post discharge: c/o SOB, cough, chest pain, asking for oxygen O/E: Hypoxemia 78% room air (SpO2 90% in 100% O2) Respiratory distress Reduce air entry on the right WCC 46 x 10^9/L CRP 32 mg/l Rx: Pip/taz & Vancomycin
32 Sept 5 Chest tube placed Bronchoscopy: Yellow secretions in right main stem bronchus Anastomosis in tact BAL sent (x1 dose abx before BAL)
33 Sept 6 Intubated in the ICU FiO2 100% BAL from Sept 5 still negative for infection
34 Question: Next steps? A) Empirical treatment with Pulse IV Methylprednisolone B) Trans-bronchial biopsies and then Pulse IV MP for ACR C) Plasmapheresis D) Continue current management while awaiting complete BAL cultures
35 Question: Next step? A) Empirical treatment with IV Methylprednisolone B) Transbronchial biopsies and then IV Methylprednisolone for ACR C) Plasmapheresis D) Continue current management while awaiting complete BAL cultures
36 Sept 6 Once stabilized: Insertion of surgical chesttube Vancomycin stopped, Pip/taz continued
37 Sept 7-8 Initial response to treatment with decreased FiO2 from 100% to 60% Extubated but requiring BIPAP and increasing FIO2 requirement Preliminary tbbx report suggestive of infection with ++neutrophils in airways EBV/CMV/fungal/adeno stains negative Antibiotics coverage broadened vancomycin, meropenam, azithromycin
38 Sept 9-10 Clinical deterioration PRAs sent urgently Received Plasmapheresis while waiting results Clinical response FiO2 90%, decreased to 60%
39 +DSAs A1 and A24 saturated (had historic weak A24) Path report Diffuse and organizing alveolar damage. Multiple distinct foci of dense perivascular mononuclear infiltrates, no capillaritis. indicative of grade A4 acute cellular rejection. Mucopururlent exudate in large airways and large airway inflammation suspicious for co-existing infection In the presence of DSAs the biopsy findings could be consistent with antibody-mediated rejection. (despite negative C4d staining)
40 5 day course of plasmapheresis with IVIG at end Increased dose of MMF Improving bilateral airspace opacification Monthly IVIg and rituximab Ongoing close monitoring of PRAs
41 REJECTION
42 Hyperacute rejection Hyperacute rejection within hours Rare, potentially catastrophic Circulating pre-formed recipient antibodies that bind to donor human leukocyte antigen (HLA) molecules on vascular endothelium, leading to vascular damage, obstruction and severe graft ischemia. Pre-op screening with virtual cross-match Sweet S and Noyes B Paediatric Lung Transplantation. In Kendig and Cherneck s Disorders of the Respiratory Tract in Children. 8th Ed.
43 Acute Cellular Rejection ACR occurs when recipient lymphocytes react with donor antigens Majority of lung transplant recipients, most common in first 3m Low early mortality but most significant RF for CLAD Non-specific clinical presentation hypoxia, fever, cough, new infiltrates, obstructive pattern on PFTs Can occur as early as one week and up to 2-3 years post Surveillance bronchs for subclinical rejection controversial Grade A2 and above Rx: Pulse Methylprednisolone x3 days Husain AN et al. Archives of pathology & laboratory medicine. 2016
44 Histologically perivascular lymphocytic infiltrates with or without airway inflammation standardized scoring none (A0) to severe (A4) Husain AN et al. Archives of pathology & laboratory medicine. 2016
45 Antibody Mediated Rejection Development of DSA s can lead to AMR AMR vs. ACR vs infection?? multidisciplinary approach to diagnosis: Clinical allograft dysfunction (can be subclinical) Circulating DSA s Pathological findings (TBBx) +/- complement 4d within the graft (C4d staining) AMR = driver of both acute and chronic lung allograft dysfunction (CLAD). No consensus on treatment strategies
46 Case 2 Consent
47 EE 3 year old boy B/G 1. Ex 37/40, MAS and NAIT in neonatal period 2. Group A Sepsis (age 2) 3. Recurrent RTI 4. Asthma 5. Mild Developmental delay
48 EE Aug 2016 Presented to ED with haematemesis GI scope In PACU frank blood in ETT Transferred to PICU I+V Bronchoscopy confirmed blood in airways
49 EE 3 year old boy CT Chest severe PVS, dilated pulmonary arteries and right ventricular hypertrophy. Ground glass opacities in RLL?fibrosing mediastinitis?primary or secondary PVS Echo: Pulmonary HTN, mildly dilated RV, RVH Good BV function (no PHTn on echo in 2015)
50 EE 3 year old boy Rx: multiple catheter interventions with balloon dilations, ASD creation Listed for Lung transplant Jan 2017 Sutureless repair of the R pulmonary veins ( ). Residual pulmonary vein stenosis post repair on CT ( ) limited response to procedures Relisted for lung transplant Treated with daily corticosteroids for unknown but potentially inflammatory aetiology July RVSp 61% systemic measured
51 EE Day 0 Donor: RLL consolidation Donor lungs underwent EVLP for borderline status CMV neg, EBV neg Transplant Uneventful ECMO - 3h Stable vascular and bronchial anastomosis on intra-op bronchoscopy Chest tubes x6
52 ACTIVATION OF INFLAMMATORY PARMAMETERS De Perrot et al. Am J Crit Care Med. 2003
53 Lungs perfused and ventilated ex-vivo at body temperature to mimic physiological conditions for 4hours If PaO2:FIO2 ratio >=350mmHg lungs considered suitable for transplant The incidence of Grade 2 or 3 PGD at 72h was 15% (n=20) compared to 30% (n=116) in the control group (p=0.11) Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. Cypel M et al. NEJM, 2011
54 EE Day 1 Hemodynamic instability inotropes Hypoxia PS18 PEEP 10cmH20 50% ino Donor BAL growing Staph Aureus (Rx Pip/taz & Vanco) Immunosuppression with IV Methylprednisolone, tacrolimus and MMF
55 Worsening pulmonary infiltrates Day 2 Day 3
56 Aetiology of pulmonary infiltrates? A) Pulmonary edema B) Infection C) Donor lung injury D) Right ventricular dysfunction E) Hyperacute cellular rejection
57 EE Day 4 Aggressive diuresis and fluid restriction Echo - RVSp 18mmHg + CVP 15cmH20 Inotropes stopped ino weaned and discontinued Vancomycin stopped (MSSA)
58 Aetiology of pulmonary infiltrates? A) Pulmonary edema B) Infection C) Donor lung injury D) Primary graft dysfunction E) Acute cellular rejection
59 Pulmonary edema Pulmonary edema common occurrence due to increased vascular permeability and severed lymphatics Management Minimize pulmonary capillary wedge pressure and central venous pressure Fluid restriction, diuresis, ino, milrinone Balanced with need to maintain systemic pressure inotropes Yeung JC et al. Cold Spring Harbor perspectives in medicine. 2014; 4:a015628
60 Primary Graft Dysfunction The expression of all the injury in the donor through to the time of reperfusion. Manifests as hypoxemia in the presence of radiographic infiltrates Typically airspace consolidation or interstitial opacities in the perihilar or basilar regions Clinically defined - ISHLT Syndrome occurring within 72 hours post lung transplant, characterized clinically by pulmonary edema and pathologically by non-specific diffuse alveolar damage Christie JD et al. The Journal of heart and lung transplantation. 2005; 24: De Perrot M et al. Am Jour Cri Care Med ;
61 Mimics Diagnosis of exclusion Cardiac dysfunction Pulmonary aspiration Infection Fluid overload Pulmonary venous outflow obstruction obstruction Antibody mediated rejection
62 PGD Overall incidence approximately 10% Grading system Graded 0-3 by the presence of radiographic infiltrates consistent with pulmonary edema and reduced oxygenation index (Pa)2/fraction of inspired O2) <300 or <200 depending on severity Christie JD et al. The Journal of heart and lung transplantation. 2005; 24:1454-9
63 PGD Treatment is supportive Intensified mechanical ventilation Inhaled Nitric Oxide Improves V/Q mismatch as NO delivered to ventilated alveoli Anti-inflammatory properties Extra-corporeal life support (ECLS) / interventional lung assist (ila) bridge to recovery Yeung JC, et al. Cold Spring Harbor perspectives in medicine. 2014; 4:a015628
64 PGD - Prognosis Significance Decreased 30 day mortality - 42% versus 6% for patients without PGD PGD contributes to nearly half of the short-term mortality after lung transplantation. Survivors of primary graft dysfunction have increased risk of death extending beyond the first post-transplant year. Increased risk of chronic allograft dysfunction Samano M, et al. Elsevier; 2012 Yeung JC, et al Cold Spring Harbor perspectives in medicine Christie JD, et al. American journal of respiratory and critical care medicine. 2005
65 EE multiple pulmonary complications Donor Lung injury (RLL consolidation) Infection (donor BAL +) Pulmonary edema Presumed acute cellular rejection Pulmonary aspiration Phrenic nerve injury
66 Summary Viable option for treatment of end-stage lung disease despite multiple complications many of which can occur in the same patient The donor pool is a limiting factor but can be improved by EVLP
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